There is a growing consensus that results generated through multiplex genetic tests, even those produced as a part of research, should be reported to providers and patients when they are considered “actionable,” that is, when they could be used to inform some potentially beneficial clinical action. However, there remains controversy over the precise criterion that should be used in identifying when a result meets this standard. In this paper, we seek to refine the concept of “actionability” by exploring one proposed (...) use for genetic test results. We argue that genetic test results indicating that a patient is at risk for developing a chronic health condition should not be considered actionable if the only potential value of that result is to motivate patients to make changes in their health behaviors. Since the empirical research currently available on this question is equivocal, we explore relevant psychological theories of human motivation to demonstrate that current theory does not support the assumption that information about genetic risk will be motivating to most patients in their attempts to make changes in health behaviors. (shrink)

Complex diseases involve both a genetic component and a response to environmental factors or lifestyle changes. Recently, genome-wide association studies (GWAS) have succeeded in identifying hundreds of polymorphisms that are statistically associated with complex diseases. However, the association is usually weak and none of the associated allelic forms is either necessary or sufficient for the disease occurrence. We argue that this promotes a network view, centred on functional redundancy. We adapted reliability theory to the concerned sub-network, modelled as a (...) parallel array of functional modules. In our model, as long as one module remains active, the function correlated with the respective disease is ensured and disease does not occur. Genetic factors reduce the initial number of available modules while environment, contingent surroundings, personal history, epigenetics, and some intrinsic stochasticity influence their persistence time. This model reproduces age-specific incidence curves and explains the influence of environmental changes. It offers a new paradigm, according to which disease occurs due to a lack of functional elements, depending on many idiosyncratic factors. Genetic risk assessed from GWAS is only a statistical notion with no direct interpretation at the individual level. However, genomic profiling could be useful at population level in devising models to guide decisions in health care policy. (shrink)

Epidemiological data suggest that previous infections can alter an individual's susceptibility to unrelated diseases. Nevertheless, the underlying mechanisms are not completely understood. Substantial research efforts have expanded the classical concept of immune memory to also include long‐lasting changes in innate immunity and antigen‐independent reactivation of adaptive immunity. Collectively, these processes provide possible explanations on how acute infections might induce long‐term changes that also affect immunity to unrelated diseases. Here, we review lasting changes the immune compartment undergoes upon infection and (...) how infection experience alters the responsiveness of immune cells towards universal signals. This heightened state of alert enhances the ability of the immune system to combat even unrelated infections but may also increase susceptibility to autoimmunity. At the same time, infection‐induced changes in the regulatory compartment may dampen subsequent immune responses and promote pathogen persistence. The concepts presented here outline how infection‐induced changes in the immune system may affect human health. (shrink)

Background and purposeWe previously established a radiological protocol to discriminate multiple system atrophy-parkinsonian subtype from Parkinson’s disease. However, we do not know if it can differentiate early stage disease. This study aimed to investigate whether the morphological and intensity changes in susceptibility weighted imaging of the lentiform nucleus could discriminate MSA-P from PD at early stages.MethodsWe retrospectively enrolled patients with MSA-P, PD and sex- and age-matched controls whose brain MRI included SWI, between January 2015 and July 2020 (...) at the Movement Disorder Center. Two specialists at the center reviewed the medical records and made the final diagnosis, and two experienced neuroradiologists performed MRI analysis, based on a defined and revised protocol for conducting morphological measurements of the LN and signal intensity.ResultsNineteen patients with MSA-P and 19 patients with PD, with less than 2 years of disease duration, and 19 control individuals were enrolled in this study. We found that patients with MSA- P presented significantly decreased size in the short line and corrected short line, ratio of the SL to the long line and corrected SLLr of the LN, increased standard deviation of signal intensity compared to patients with PD and controls. With receiver operating characteristic analysis, this finding had a sensitivity of 89.5% and a specificity of 73.7% to distinguish MSA- P from PD.ConclusionCompared to PD and controls, patients with MSA-P are characterized by a narrowing morphology of the posterior region of the LN. Quantitative morphological changes provide a reference for clinical auxiliary diagnosis. (shrink)

The aim of the present paper is to explore whether seasonal outbreaks of infectious diseases may be linked to changes in host microbiomes. This is a very important issue, because one way to have more control over seasonal outbreaks is to understand the factors that underlie them. In this paper, I will evaluate the relevance of the microbiome as one of such factors. The paper is based on two pillars of reasoning. Firstly, on the idea that microbiomes play an important (...) role in their hosts’ defence against infectious diseases. Secondly, on the idea that microbiomes are not stable, but change seasonally. These two ideas are combined in order to argue that seasonal changes in a given microbiome may influence the functionality of the host's immune system and consequently make it easier for infectious agents to infect the host at certain times of year. I will argue that, while this is only a theoretical possibility, certain studies may back up such claims. Furthermore, I will show that this does not necessarily contradict other hypotheses aimed at explaining seasonal outbreaks; in fact, it may even enhance them. (shrink)

Recombinant DNA technology can now be applied to the analysis of complex human diseases such as polygenic disorders, where the inheritance of several unknown genes appears to be involved. We review here the progress in the analysis of genes which may be involved in the development of hyperlipidaemia, and show how the approach may be important in our understanding of the aetiology of coronary artery disease.

The susceptibility of decision-makers’ choices to variations in option framing has been attributed to individual differences in cognitive style. According to this view, individuals who are prone to a more deliberate, or less intuitive, thinking style are less susceptible to framing manipulations. Research findings on the topic, however, have tended to yield small effects, with several studies also being limited in inferential value by methodological drawbacks. We report two experiments that examined the value of several cognitive-style variables, including measures (...) of cognitive reflection, subjective numeracy, actively open-minded thinking, need for cognition, and hemispheric dominance, in predicting participants’ frame-consistent choices. Our experiments used an isomorph of the Asian Disease Problem and we manipulated frames between participants. We controlled for participants’ sex and age, and we manipulated the order in which choice options were presented to participants. In Experiment 1 (N = 190) using an undergraduate sample and in Experiment 2 (N = 316) using a sample of Amazon Mechanical Turk workers, we found no significant effect of any of the cognitive style measures taken on predicting frame-consistent choice, regardless of whether we analyzed participants’ binary choices or their choices weighted by the extent to which participants preferred their chosen option over the non-chosen option. The sole factor that significantly predicted frame consistent choice was framing: in both experiments, participants were more likely to make frame consistent choices when the frame was positive than when it was negative, consistent with the tendency towards risk aversion in the task. The present findings do not support the view that individual differences in people’s susceptibility to framing manipulations can be substantially accounted for by individual differences in cognitive style. (shrink)

Human beings are essentially vulnerable in the view that their existence qua humans is not given but construed. This vulnerability receives basic protection from the State, expressed in the form of the universal rights all citizens are meant to enjoy. In addition, many individuals fall prey to destitution and deprivation, requiring social action aimed at recognising the specific harms they suffer and providing remedial assistance to palliate or remove their plights.Citizens receive protection against their biologic vulnerability by means of an (...) in rem right to health [care], which is more an attitude of protection than a specific programme. When individuals become susceptible, that is, biologically weak or diseased, they also increase their predisposition to additional harm, and require social actions to treat their demeaned condition. Such assistance takes the form of positive healthcare rights.Research on human beings has been slow to observe that the subjects recruited are susceptible, especially so if research is done in less developed countries. By mislabelling them as vulnerable – a characteristic they share with all humans – sponsors avoid registering the deprivation these people suffer, and the ethical obligation to offer them remedial help.The distinction between vulnerability and susceptibility also marks the difference between being intact but fragile – vulnerable – and being injured and predisposed to compound additional harm – susceptible. Awareness of this difference should give additional force to the rejection of double standards in research ethics. (shrink)

The susceptible-transmissible-removed (STR) model is a deterministic compartment model, based on the susceptible-infected-removed (SIR) prototype. The STR replaces 2 SIR assumptions. SIR assumes that the emigration rate (due to death or recovery) is directly proportional to the infected compartment’s size. The STR replaces this assumption with the biologically appropriate assumption that the emigration rate is the same as the immigration rate one infected period ago. This results in a unique delay differential equation epidemic model with the delay equal to the (...) infected period. Hamer’s mass action law for epidemiology is modified to resemble its chemistry precursor—the law of mass action. Constructing the model for an isolated population that exists on a surface bounded by the extent of the population’s movements permits compartment density to replace compartment size. The STR reduces to a SIR model in a timescale that negates the delay—the transmissible timescale. This establishes that the SIR model applies to an isolated population in the disease’s transmissible timescale. Cyclical social interactions will define a rhythmic timescale. It is demonstrated that the geometric mean maps transmissible timescale properties to their rhythmic timescale equivalents. This mapping defines the hybrid incidence (HI). The model validation demonstrates that the HI-STR can be constructed directly from the disease’s transmission dynamics. The basic reproduction number (R0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathcal{R}}_0$$\end{document}) is an epidemic impact property. The HI-STR model predicts that R0∝ρnB\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathcal{R}}_0 \propto \root \mathfrak{B} \of {\rho_n}$$\end{document} where ρn\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\rho_n$$\end{document} is the population density, and B\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathfrak{B}}$$\end{document} is the ratio of time increments in the transmissible- and rhythmic timescales. The model is validated by experimentally verifying the relationship. R0\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathcal{R}}_0$$\end{document}’s dependence on ρn\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\rho_n$$\end{document} is demonstrated for droplet-spread SARS in Asian cities, aerosol-spread measles in Europe and non-airborne Ebola in Africa. (shrink)

Lentinus edodes sticks are susceptible to mold infection during the culture process, and manual identification of infected sticks is heavy, untimely, and inaccurate. Aiming to solve this problem, this paper proposes a method for identifying infected Lentinus edodes sticks based on improved ResNeXt-50 deep transfer learning. First, a dataset of Lentinus edodes stick diseases was constructed. Second, based on the ResNeXt-50 model and the pretraining weight of the ImageNet dataset, the influence of pretraining weight parameters on recognition accuracy was studied. (...) Finally, six fine-tuning strategies of the fully connected layer were designed to modify the fully connected layer of ResNeXt-50. The experimental results show that the recognition accuracy of the method proposed in this paper can reach 94.27%, which is higher than the Vgg16, GoogLeNet, ResNet50, and MobileNet v2 models by 8.47%, 6.49%, 4.68%, and 9.38%, respectively, and the F1-score can reach 0.9422. The improved method proposed in this paper can reduce the calculation pressure and overfitting problem of the model, improve the accuracy of the model in the identification of Lentinus edodes stick mold diseases, and provide an effective solution for the selection of diseased sticks. (shrink)

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as “missing heritability.” Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each (...) one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases. (shrink)

Atmospheric pollution is deteriorating, which has affected the evolution of respiratory disease for the exposed human worldwide. Thus, exploring the influence of air pollution on the evolution of disease transmission dynamics is a significant issue. In this article, a stochastic susceptible-infective epidemic model in a polluted atmospheric environment is investigated. The existence and uniqueness of the global positive solution are established. In virtue of the aggregation methods and Lyapunov function, the sufficient conditions of disease extinction, persistence, and (...) existence of the stationary distribution are established, respectively. TakingPM2.5concentration as the air pollutant index, numerical simulations are carried out to support these results. Our results indicated that the disease transmission dynamics are significantly associated with the environmental atmospheric pollution and fluctuation. (shrink)

Theiler's virus is a picornavirus of mouse which causes an acute encephalomyelitis followed by a persistent infection of the white matter resulting in chronic inflammation and demyelination. This disease has been studied as a model for multiple sclerosis. Inbred strains of mice are either resistant--they clear the infection after the acute encephalomyelitis--or susceptible to persistent infection and demyelination. Susceptibility is a polygenic trait which has been analyzed using methods of association with “candidate” genes, and linkage analysis after a (...) complete genome scan. The H-2Db gene is responsible for an efficient CTL response which makes some strains resistant. Non H-2 genes responsible for the susceptibility of other strains have been mapped by linkage analysis to the Ifng and, possibly, the Mbp loci. The analysis of a set of congenic mice ruled out the possiblity that the relevant gene codes for interferon gamma, and showed that the region around Ifngprobably contains two susceptibility genes. The analysis of mutant mice showed further that the Mbp gene, which codes for the myelin basic protein, has a major effect on viral persistence. BioEssays 20:627–633, 1998. © 1998 John Wiley & Sons Inc. (shrink)

The expanded use of genetic testing raises key ethical and policy questions about possible benefits and harms for those receiving disease‐risk information. As predictive testing for Huntington’s was initiated in a clinical setting, survey research posing hypothetical test scenarios suggested that the vast majority of at‐risk relatives wanted to know whether they carried a disease‐causing mutation. However, only a small minority ultimately availed themselves of this opportunity. Many at‐risk individuals concluded that a positive test result would be too (...) psychologically overwhelming. A substantial literature suggests that individuals are often more resilient than anticipated in coping with many different health‐related stresses. Much of my own work in the field has been through the Risk Evaluation & Education for Alzheimer’s Disease study (REVEAL), a series of randomized clinical trials assessing the impact of genetic susceptibility testing on asymptomatic individuals at risk for Alzheimer’s disease. Our experience in developing and implementing four successive, multisite trials provides some potentially useful lessons for the field. More people will be asking for their personal genetic information. Better understanding will help us decide when access is appropriate and how best to disclose results in a manner that supports adjustment to test findings and promotes use of genetic information to improve human health. (shrink)

On ‘Mismatch’ and ‘Metabolic Ghettos:’ The Conceptualization of Global Health Differences in Research on the Developmental Origins of Health and Disease. Epigenetic approaches to human health have received growing attention in the past two decades. They allow to view the development of human organisms as plastic, i.e. as open to influences from the social and material environment such as nutrition, stress, and trauma. This has lent new credence to approaches in biomedicine that aim to draw attention to the importance (...) of development for later life health. Some scholars in the social sciences and humanities have welcomed such approaches as a departure from gene‐centric perspectives and as an opportunity for highlighting the social and political determinants of health and illness. Others have warned that they might lead to new forms of biological reductionisms and determinisms. In this article, we explore how research on developmental plasticity addresses and articulates global health disparities, specifically in the context of postcolonial India. We discuss two prominent approaches from the field of Developmental Origins of Health and Disease (DOHaD) that build on epigenetic perspectives on health and illness and view different global rates of disease susceptibility as the result of developmental processes: first, the ‘mismatch paradigm’ by Peter Gluckman and Mark Hanson and second, the ‘metabolic ghetto’ concept by Jonathan Wells. We highlight how both approaches render historical and social factors meaningful for the development of global health disparities, but emphasize how they at the same time remain prone to determinisms and reductionisms reminiscent of a gene‐centric perspective. DOHaD actors themselves are critical of these tendencies, and in conclusion we explore novel opportunities for interdisciplinary collaborations enabled by this critical potential. (shrink)

Modelling contagious diseases needs to include a mechanistic knowledge about contacts between hosts and pathogens as specific as possible, e.g., by incorporating in the model information about social networks through which the disease spreads. The unknown part concerning the contact mechanism can be modelled using a stochastic approach. For that purpose, we revisit SIR models by introducing first a microscopic stochastic version of the contacts between individuals of different populations (namely Susceptible, Infective and Recovering), then by adding a random (...) perturbation in the vicinity of the endemic fixed point of the SIR model and eventually by introducing the definition of various types of random social networks. We propose as example of application to contagious diseases the HIV, and we show that a micro-simulation of individual based modelling (IBM) type can reproduce the current stable incidence of the HIV epidemic in a population of HIV-positive men having sex with men (MSM). (shrink)

Cancer susceptibility testing is likely to become routine in medical practice, despite many limitations and unanswered questions. These uncertainties greatly complicate the process of informed consent, creating an excellent opportunity to reconsider exactly how it should be conducted. Research with women's reactions to the availability of genetic susceptibility testing for breast cancer dramatically underscores that informed consent ought to be highly individualized, taking care to discern what patients believe about the disease and its causes and what role (...) they want their physician to play. (shrink)

Almost every human disease has both a genetic and an environmental component. Even a classical inherited condition such as hemophilia can be influenced by external factors—in fact, most of the pathogenic effects of the mutation can be avoided by judicious injections of clotting factor, leading to a nearly normal life expectancy. For infectious diseases, often considered as essentially environmental, there are well-documented inherited differences in susceptibility, one of the most striking being the resistance to HIV infection of homozygous (...) carriers of the delta-32 mutation in the CCR5 gene (Dragic et al. 1996). Nevertheless, a number of conditions are “mostly genetic,” others “mostly environmental,” while many .. (shrink)

Race and ethnicity are well-established epidemiological categories that relate to the patients’ risk of exposure and their susceptibility/resistance to disease. However, this association creates the notion that factors other than a personal identity need not be held responsible for patients’ health problems. This work deconstructs the notion of race and ethnicity as risk factors for immigrant ill health, which is prevalent in current medical research and practice, by tracing its roots in Canadian history. The understanding that medical knowledge (...) is subject to diverse historical, social, cultural and political influences can change the way health professionals perceive their patients as a health threat. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Aging, Chance, and RaceAtwood D. Gaines (bio)KeywordsAlzheimer’s disease, chance, mild cognitive impairment, racism, social constructionsThomas Kirkwood's comments are a welcome, articulate detailing of how and why we age with special reference to the brain. As well, his paper indicates clearly that processes reified as pathology and disease, such as Alzheimer's disease (AD), are in fact common and inevitable as the human brain ages. (...) Doubtless, this is the reason that aging is by far the greatest risk factor for the development of AD. A key notion, briefly mentioned by Kirkwood, is that of chance. He points out that, "cells (will be) burdened with protein aggregates and similar materials that will increase with aging. Once again, which cells will experience this fate and which will continue to function healthily is strongly influenced by chance" (Kirkwood 2006, 80–81). This mention of chance is most important for our paper, "Building a Mystery," and for an understanding of science as well. In "Building a Mystery," Peter Whitehouse and I sought to show that the history of AD was not inevitable and demonstrates a variety of chance and singular decisive occurrences of encounters, interpretations, social movements, government initiatives, and technological developments. Such decisive moments do not occur by virtue of some (natural) lawful process that is unfolding, but rather, these are chance events that could have happened in other ways. Indeed, science has been viewed as human attempts to "tame chance" (Hacking 1990). However, it often does so by sleight of hand, misinterpretation, and the biomedical discourse of hope. Increasingly, we are learning that chance is a commonality, not a rarity, in social and biological domains. The biomedical approach assumes the opposite. For example, it seeks to tame the chance appearance of AD in the case of Auguste D, and does so in part by reifying differences that exist, as Kirkwood notes, along a continuum rather than as the discrete entities implied by the labels Alzheimer's disease or mild cognitive impairment (MCI).We thus stand with Kirkwood's bold recognition of chance (see also Kirkwood 2003) in the biological domain and have applied the same idea to the social domain in which we consider the practice of biomedical science. We have elsewhere emphasized consensus statements in the making of AD (Gaines and Whitehouse 1998). In the present article, we add a number of other chance, decisive sociocultural moments to the mix of social processes producing AD and MCI. We have not considered in detail here a host of cultural features in the theory and practice of biomedicine with respect to AD. These include implicit, yet highly [End Page 83] implicative, cultural notions of bilateral kinship employed in genetic research on AD considered elsewhere (Gaines 1998).Bavidge's comments are cogent as well. With respect to the notion of my concept of the local biology of "race" (Gaines 2005), it is germane to point out here that such culturally constructed biologies are relevant to a discussion of AD and other dementias. Such constructions represent culture in science. We used the dramatic example of "race" in US biomedicine because it is experiencing a resurgence as an explanatory tool. For example, recently Haiman et al. (2006) presented research that suggests that "Among cigarette smokers, African Americans and native Hawaiians are more susceptible to lung cancer than whites, Japanese Americans and Latinos." The authors assert, as have many US studies, that their findings show differences relate to the alleged biology of the social groups concerned. Their problem and that of others, is that the groups are social, not biological, and most have mixed ancestry and do not stem from distinct groups. This is particularly true of African Americans and Latinos; both groups are substantially composed of individuals with European, West African, and Native American ancestry in widely varying proportions (Gaines 2005). Thus, they are different only in terms of their classification. Such work regularly overlooks influences, such as environmental racism, discrimination, poverty, and a lack of medical care, as well as other practices. These might include, in a study of smoking, pakalolo smoking (local marijuana) among Hawaiians, who themselves are usually part Portuguese, Japanese, Chinese, and or European... (shrink)

Leishmania major infection of inbred mice leads to a major dichotomous response—death or survival—that depends on the strain of mice. This finding has motivated efforts to locate genetic determinants of disease susceptibility. Genotyping studies have confirmed a complex multilocus trait, but studies directed at the biology of the response suggest identifiable components of susceptibility that may direct the genetic investigations. A confluence of parasite variables—residence in macrophages, class II-dependent immunity, and avoidance of early IL-12 induction—with host factors—a (...) prominent helper T-cell precursor frequency to a dominant parasite epitope and a bias in IL-4 gene activation—conspires to drive an aberrant immune response in animals that suffer fatal disease. These insights may lead to an understanding of factors that focus responses on dominant antigens and that mold the naive T-cell repertoire. Collectively, such factors might contribute to the pathogenesis of other infectious and autoimmune diseases. BioEssays 21:510–518, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a (...) perspective on this debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

In recent years, an increasing number of medical books and papers attempting to analyse the concepts of health and disease from the perspective of evolutionary biology have been published.This paper introduces the evolutionary approach to health and disease in an attempt to illuminate the premisses and the framework of Darwinian medicine. My primary aim is to analyse to what extent evolutionary theory provides for a biological definition of the concept of disease. This analysis reveals some important differences (...) between functional explanations in the field of evolutionary biology and functional explanations in the field of medicine. Moreover, I shall argue that the biological functions relevant to the health of an organism cannot be determined on the basis of evolutionary theory. Accordingly, it seems that Darwinian medicine does not provide for the definition of a biological concept of disease. Still,Darwinian medicine may suggest why we are susceptible to certain diseases; it might also prove a suggestive heuristic on the basis of which new hypotheses concerning relevant treatments of various diseases might be advanced. (shrink)

Exact solutions of epidemic models are critical for identifying the severity and mitigation possibility for epidemics. However, solving complex models can be difficult when interfering conditions from the real-world are incorporated into the models. In this paper, we focus on the generally unsolvable adaptive susceptible-infected-susceptible epidemic model, a typical example of a class of epidemic models that characterize the complex interplays between the virus spread and network structural evolution. We propose two methods based on mean-field approximation, i.e., the first-order mean-field (...) approximation and higher-order mean-field approximation, to derive the exact solutions to ASIS models. Both methods demonstrate the capability of accurately approximating the metastable-state statistics of the model, such as the infection fraction and network density, with low computational cost. These methods are potentially powerful tools in understanding, mitigating, and controlling disease outbreaks and infodemics. (shrink)

Differences in perceptions and knowledge of crop diseases constitute a major obstacle in farmer–researcher cooperation, which is necessary for sustainable disease management. Farmers’ perceptions and management of crop diseases in the northern Ethiopian Regional State of Tigrai were investigated in order to harness their knowledge in the participatory development of integrated disease management (IDM) strategies. Knowledge of disease etiology and epidemiology, cultivar resistance, and reasons for the cultivation of susceptible cultivars were investigated in a total of 12 (...) tabias (towns) in ten weredas (districts). Perception of diseases involved both scientific and spiritual conceptual frameworks. Of the more than 30 crop diseases recorded on the major crops in the region, only rusts and powdery mildews (locally called humodia) and a few root rots were considered by farmers to be important. Farmers’ awareness of other diseases was extremely low; some highly damaging but less conspicuous diseases, such as faba bean chocolate spot and chickpea ascochyta blight (also called humodia), were not regarded by farmers as disease but as problems caused primarily by excessive soil moisture. Considering that some of these “unrecognized” diseases can cause complete yield loss and genetic erosion in epiphytotic years, there is an urgent need for bringing together farmers’ and scientists’ knowledge to complement each other. Even when farmers had access to disease-resistant or disease-tolerant cultivars, they grew susceptible local varieties because of multiple criteria including earliness, good yield in years with low humodia severity, suitability for home consumption, market demand/quality, and low soil fertility and land management requirements. Farmer innovation and knowledge were evident in their use of diverse disease control measures, but these were a mixture of the “useful and the useless.” Our findings stress the necessity for extension workers and researchers to understand and improve farmers’ knowledge of crop diseases, and farmers’ ability to observe and experiment, through the Farmer Field School or a similar experiential learning approach. These insights about farmers’ knowledge of crop diseases provide a basis for further collaborative maintenance of crop genetic diversity, development of germplasm, and IPM-related research in Africa. (shrink)

That there is a heritable or familial component of susceptibility to chronic non‐communicable diseases such as type 2 diabetes, obesity and cardiovascular disease is well established, but there is increasing evidence that some elements of such heritability are transmitted non‐genomically and that the processes whereby environmental influences act during early development to shape disease risk in later life can have effects beyond a single generation. Such heritability may operate through epigenetic mechanisms involving regulation of either imprinted or (...) non‐imprinted genes but also through broader mechanisms related to parental physiology or behaviour. We review evidence and potential mechanisms for non‐genomic transgenerational inheritance of ‘lifestyle’ disease and propose that the ‘developmental origins of disease’ phenomenon is a maladaptive consequence of an ancestral mechanism of developmental plasticity that may have had adaptive value in the evolution of generalist species such as Homo sapiens. BioEssays 29: 145–154, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Neurodegenerative Parkinson's Disease is one of the common incurable diseases among the elderly. Clinical assessments are characterized as standardized means for PD diagnosis. However, relying on medical evaluation of a patient's status can be subjective to physicians' experience, making the assessment process susceptible to human errors. The use of ICT-based tools for capturing the status of patients with PD can provide more objective and quantitative metrics. In this vein, the Personalized Serious Game Suite and intelligent Motor Assessment Tests, produced (...) within the i-PROGNOSIS European project, are explored in the current study. More specifically, data from 27 patients with PD at Stage 1 and Stage 3 produced from their interaction with PGS/iMAT are analyzed. Five feature vector scenarios are set, including features from PGS or iMAT scores or their combination, after also taking into consideration the age of patients with PD. These FVs are fed into three machine learning classifiers, i.e., K-Nearest Neighbor, Support Vector Machines, and Random Forest, to infer the stage of each patient with PD. A Leave-One-Out Cross-Validation method is adopted for testing the classification performance. The experimental results show that a high classification accuracy is achieved from both data sources, justifying the effectiveness of PGS/iMAT to efficiently reflect the motor skill status of patients with PD and further potentiating PGS/iMAT enhancement with a machine learning a part to infer for the stage of patients with PD. Clearly, this integrated approach provides new opportunities for remote monitoring of the stage of patients with PD, contributing to a more efficient organization and set up of personalized interventions. (shrink)

ABSTRACT Because of the nature of preventive vaccination programs, the viability of these public health interventions is particularly susceptible to public perceptions. This is because vaccination relies on a concept of ‘herd immunity’, achievement of which requires rational public behavior that can only be obtained through full and accurate communication about risks and benefits. This paper describes how irrational behavior that threatens the effectiveness of vaccination programs – both in crisis and non‐crisis situations – can be tied to public perceptions (...) created by media portrayals of health risks. I concentrate on childhood vaccination as an exemplar of ‘non‐crisis’ preventive vaccination, and on the recent flu vaccine shortage as a ‘crisis’ situation. The paper concludes with an examination of the steps necessary to resolve these threats through better public communication. (shrink)

A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell–mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of medullary thymic (...) epithelial cells that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC, T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases. IKK/NF-κB regulates the expression of many genes that encode proteins involved in many crucial biological functions, such as immunity, tissue homeostasis, and fungal/bacterial/viral infections. Also, IKKα plays anti-tumor activities in many organs independently of NF-κB pathways. Thus, an inborn error in one of these gene loci can cause severe human diseases through these complicated mechanisms. (shrink)

Alzheimer’s disease is an example of age-related dementia, and there are still no known preventive or curative measures for this disease. Obesity and associated metabolic changes are widely accepted as risk factors of age-related cognitive decline. Insulin is the prime mediator of metabolic homeostasis, which is impaired in obesity, and this impairment potentiates amyloid-β accumulation and the formation of neurofibrillary tangles. Obesity is also linked with functional and morphological alterations in brain mitochondria leading to brain insulin resistance and (...) memory deficits associated with AD. Also, increased peripheral inflammation and oxidative stress due to obesity are the main drivers that increase an individual’s susceptibility to cognitive deficits, thus doubling the risk of AD. This enhanced risk of AD is alarming in the context of a rapidly increasing global incidence of obesity and overweight in the general population. In this review, we summarize the risk factors that link obesity with AD and emphasize the point that the treatment and management of obesity may also provide a way to prevent AD. (shrink)

Cytokines, also referred to as interleukins, are the major orchestrators of host defence processes, and, as such, are involved in insults, repair and restoration of tissue homeostasis. This review summarises recent findings on and emerging models of the biological roles of the double-edged sword interleukin-13 (IL-13), which have been principally obtained from studies in mice that are deficient for IL-13, or its components. IL-13-mediated functions not only contribute to the susceptible phenotype in Leishmania major infection but also seem to play (...) a protective role in chronic leishmaniasis. Moreover, IL-13 plays a key protective role in the expulsion of helminths from the gut while also actively contributing to the pathology in schistosomiasis. In allergic asthma, IL-13 has also been found to be a key factor. Therapeutic administration of an IL-13 inhibitor in mice successfully prevents both the allergic disease phenotype and schistosoma egg-induced lung pathology. If this scenario holds true in humans, we soon may have an efficient drug for treatment of IL-13-mediated diseases. BioEssays 22:646–656, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

A paradigm shift in the human chronotoxicity of xenobiotics would study two‐sided desynchronized phenomena of interfacial interactions between cyclic or periodic environmental insults and the endogenous response and recovery profile. These systems‐based networks are under the influence of well‐synchronized biological clocks and their metabolic regulators. This perspective argues in favor of addressing the concept of synchronization in studies involving critical life windows of susceptibility, or circadian rhythms, or 24‐hour (periodic) diurnal rhythms and answering whether these disruptions in synchronization would (...) affect response and recovery or disease phenotypes associated with environmental insults, e.g., xenobiotics. Synchronization or synchrony is defined as the totality of elements that appear during the same time period within a system, including the network of interactions between the system's elements. Desynchronized interfaces during critical life windows or in time‐repeated exposure events would likely lead to initiating a cascade of adverse health effects associated with differentiated disease phenotypes. (shrink)

Delineation of the subthalamic nuclei on MRI is critical for deep brain stimulation surgery in patients with Parkinson’s disease. We propose this retrospective cohort study for quantitative analysis of MR signal-to-noise ratio, contrast, and signal difference-to-noise ratio of the STN on pre-operative three-dimensional stereotactic MRI in patients with medication-refractory PD. Forty-five consecutive patients with medication-refractory PD who underwent STN-DBS surgery in our hospital from January 2018 to June 2021 were included in this study. All patients had whole-brain 3D MRI, (...) including T2-weighted imaging, T2-weighted fluid-attenuated inversion recovery, and susceptibility-weighted imaging, at 3.0 T scanner for stereotactic navigation. The signal intensities of the STN, corona radiata, and background noise were obtained after placing regions of interest on corresponding structures. Quantitative comparisons of SNR, contrast, and SDNR of the STN between MR pulse sequences, including the T2WI, FLAIR, and SWI. Subgroup analysis regarding patients’ sex, age, and duration of treatment. We used one-way repeated measures analysis of variance for quantitative comparisons of SNR, contrast, and SDNR of the STN between different MR pulse sequences, and we also used the dependent t-test for the post hoc tests. In addition, we used Mann–Whitney U test for subgroup analyses. Both the contrast and SDNR were highest on FLAIR. The SNR was highest on SWI, and both the SNR and SDNR were lowest on T2WI. Subgroup analyses demonstrated significantly lower SDNR on SWI for patients receiving medication treatment for ≥13 years. In conclusion, on 3D stereotactic MRI of medication-refractory PD patients, the contrast and SDNR for the STN are highest on FLAIR, suggesting the optimal delineation of STN on FLAIR. (shrink)

This chapter considers ethical issues involved in genetic testing and screening for susceptibility to various forms of cancer.

Because of the nature of preventive vaccination programs, the viability of these public health interventions is particularly susceptible to public perceptions. This is because vaccination relies on a concept of ‘herd immunity’, achievement of which requires rational public behavior that can only be obtained through full and accurate communication about risks and benefits. This paper describes how irrational behavior that threatens the effectiveness of vaccination programs – both in crisis and non-crisis situations – can be tied to public perceptions created (...) by media portrayals of health risks. I concentrate on childhood vaccination as an exemplar of ‘non-crisis’ preventive vaccination, and on the recent flu vaccine shortage as a ‘crisis’ situation. The paper concludes with an examination of the steps necessary to resolve these threats through better public communication. (shrink)

Public discussions of ethical issues related to the biotechnology industry tend to treat “biotechnology” as a single, undifferentiated technology. Similarly, the pros and cons associated with this entire sector tend to get lumped together, such that individuals and groups often situate themselves as either “pro-” or “anti-” biotechnology as a whole. But different biotechnologies and their particular application context pose very different challenges for ethical corporate decision-making. Even within a single product category, different specialty products can pose strikingly different ethical (...) challenges. In this paper, we focus on the single over-arching category of “genetic testing” and compare tests for disease susceptibility and drug response. We highlight the diversity of ethical challenges – grouped under the broad categories of “truth in advertising” and “protecting intellectual property” – raised by the commercialization and marketing of these technologies. By examining social and technical differences between genetic tests, and the associated corporate ethics challenges posed by their commercialization, our intent is to contribute to the nascent business ethics literature examining issues raised by the development and marketing of genetic tests. (shrink)

Background The rise in genomic and biobanking research worldwide has led to the development of different informed consent models for use in such research. This study analyses consent documents used by investigators in the H3Africa (Human Heredity and Health in Africa) Consortium. Methods A qualitative method for text analysis was used to analyse consent documents used in the collection of samples and data in H3Africa projects. Thematic domains included type of consent model, explanations of genetics/genomics, data sharing and feedback of (...) test results. Results Informed consent documents for 13 of the 19 H3Africa projects were analysed. Seven projects used broad consent, five projects used tiered consent and one used specific consent. Genetics was mostly explained in terms of inherited characteristics, heredity and health, genes and disease causation, or disease susceptibility. Only one project made provisions for the feedback of individual genetic results. Conclusion H3Africa research makes use of three consent models—specific, tiered and broad consent. We outlined different strategies used by H3Africa investigators to explain concepts in genomics to potential research participants. To further ensure that the decision to participate in genomic research is informed and meaningful, we recommend that innovative approaches to the informed consent process be developed, preferably in consultation with research participants, research ethics committees and researchers in Africa. (shrink)

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 and X-linked CLDN2 through a two-stage genome-wide study. The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk (...) allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men. © 2012 Nature America, Inc. All rights reserved. (shrink)

This paper is intended to stimulate debate amongst stakeholders in the international research community on the topic of returning individual genetic research results to study participants. Pharmacogenetics and disease genetics studies are becoming increasingly prevalent, leading to a growing body of information on genetic associations for drug responsiveness and disease susceptibility with the potential to improve health care. Much of these data are presently characterized as exploratory (non‐validated or hypothesis‐generating). There is, however, a trend for research participants (...) to be permitted access to their personal data if they so choose. Researchers, sponsors, patient advocacy groups, ethics committees and regulatory authorities are consequently confronting the issue of whether, and how, study participants might receive their individual results. Noted international ethico‐legal guidelines and public policy positions in Europe and the United States are reviewed for background. The authors offer ‘Points‐to‐Consider’ regarding returning research results in the context of drug development trials based on their knowledge and experience. These considerations include: the clinical relevance of data, laboratory qualifications, informed consent procedures, confidentiality of medical information and the competency of persons providing results to participants. The discussion is framed as a benefit‐to‐risk assessment to balance the potential positive versus negative consequences to participants, while maintaining the integrity and feasibility of conducting genetic research studies. (shrink)

Confusions about the place of race in medicine result in part from a failure to recognize the plurality of race concepts. Recognition that the ordinary concept of race is not identical to the racialist concept of race makes it possible to ask whether there might be a legitimate place for the deployment of concepts of race in medical contexts. Two technical race concepts are considered. The concept of social race is the concept of a social group that is taken to (...) be a racialist race. It is apt for use in examining and addressing the medical effects of discrimination. The populationist concept of race represents race as a kind of biological population. It makes it possible to frame the question whether biological race is a factor in disease susceptibility and drug responsiveness. It is apt for use in determining whether biological race is a medically significant category. (shrink)

ABSTRACT This paper is intended to stimulate debate amongst stakeholders in the international research community on the topic of returning individual genetic research results to study participants. Pharmacogenetics and disease genetics studies are becoming increasingly prevalent, leading to a growing body of information on genetic associations for drug responsiveness and disease susceptibility with the potential to improve health care. Much of these data are presently characterized as exploratory (non‐validated or hypothesis‐generating). There is, however, a trend for research (...) participants to be permitted access to their personal data if they so choose. Researchers, sponsors, patient advocacy groups, ethics committees and regulatory authorities are consequently confronting the issue of whether, and how, study participants might receive their individual results. Noted international ethico‐legal guidelines and public policy positions in Europe and the United States are reviewed for background. The authors offer ‘Points‐to‐Consider’ regarding returning research results in the context of drug development trials based on their knowledge and experience. These considerations include: the clinical relevance of data, laboratory qualifications, informed consent procedures, confidentiality of medical information and the competency of persons providing results to participants. The discussion is framed as a benefit‐to‐risk assessment to balance the potential positive versus negative consequences to participants, while maintaining the integrity and feasibility of conducting genetic research studies. (shrink)

Biobanks are currently archiving human materials for medical research at a hitherto unprecedented rate. These valuable resources will be essential for developing ‘personalized’ medicines and for a better understanding of disease susceptibilities. However, for such scientific advances to benefit everyone, it is crucial that biobanks recruit donations from all sections of the community. Unfortunately, other initiatives, such as transplant programmes, have clearly demonstrated that ethnic minorities are under-represented. Here we suggest that this issue deserves serious consideration to avoid biobanks (...) evolving into ethnically biased archives which unwittingly promote race-specific research. Specifically, this necessitates research ethics committees engaging in a re-assessment of the relative merits of individual personal sovereignty and the common good. (shrink)

Background: The search for genetic variants between racial/ethnic groups to explain differential disease susceptibility and drug response has provoked sharp criticisms, challenging the appropriateness of using race/ethnicity as a variable in genetics research, because such categories are social constructs and not biological classifications.Objectives: To gain insight into how a group of genetic scientists conceptualise and use racial/ethnic variables in their work and their strategies for managing the ethical issues and consequences of this practice.Methods: In-depth semi-structured interviews were conducted (...) with a purposive sample of 30 genetic researchers who use racial/ethnic variables in their research. Standard qualitative methods of content analysis were used.Results: Most of the genetic researchers viewed racial/ethnic variables as arbitrary and very poorly defined, and in turn as scientifically inadequate. However, most defended their use, describing them as useful proxy variables on a road to “imminent medical progress”. None had developed overt strategies for addressing these inadequacies, with many instead asserting that science will inevitably correct itself and saying that meanwhile researchers should “be careful” in the language chosen for reporting findings.Conclusions: While the legitimacy and consequences of using racial/ethnic variables in genetics research has been widely criticised, ethical oversight is left to genetic researchers themselves. Given the general vagueness and imprecision we found amongst these researchers regarding their use of these variables, they do not seem well equipped for such an undertaking. It would seem imperative that research ethicist move forward to develop specific policies and practices to assure the scientific integrity of genetic research on biological differences between population groups. (shrink)

Fritz Allhoff has recently offered an extremely compelling challenge to the morality of human cloning. He argues that a biological phenomenon, that of telomere shortening, undermines the moral permissibility of human cloning. Telomere shortening is caused by cell replication, and appears to be one of the central reasons that cells and organisms age and die. Allhoff considers a thirty-year-old woman who wishes to create a genetic clone. He notes that the DNA from her cell that would be used to create (...) the clone would have shortened telomeres—as it would have gone through many generations of cell replication. As a result, the clone would begin its existence with shortened telomeres; the clone’s telomeres would be the same length as the woman’s telomeres at the time of cloning. The moral problem lies in the fact that because of shortened telomeres, the clone will senesce more rapidly as compared with noncloned organisms, and would have increased susceptibility to degenerative conditions and diseases. Allhoff then goes on to argue that earlier senescence and disease susceptibility constitute a moral ground for rejecting cloning because “the life of a clone would be worse than that of a non-clone”. This line of argument is rooted in Parfit’s The Same Number Quality Claim : “If in either of two outcomes the same number of people would ever live, it would be bad if those who live are worse off, or have a lower quality of life, than those who would have lived”. Applying Parfit’s Q principle to cases of cloning, it could be argued that parents ought to produce children that would be maximally well off, and since clones would be worse off than children produced “normally,” it follows that parents should avoid cloning. As Allhoff puts it, “obviously sexual reproduction would not transfer shortened telomeres to offspring so, all else being equal, sexual reproduction is better than cloning ”. For this sort of line to pack any moral punch, Q must be interpreted rather strongly. (shrink)

The identification and avoidance of disease susceptibility in embryos is the most common goal of preimplantation genetic diagnosis (PGD). Most jurisdictions that accept but regulate the availability of PGD restrict it to what are characterized as ‘serious’ conditions. Line-drawing around seriousness is not determined solely by the identification of a genetic mutation. Other factors seen to be relevant include: impact on health or severity of symptoms; degree of penetrance (probability of genotype being expressed as a genetic disorder); potential (...) for therapy; rate of progression; heritability; and age of onset. In the original applications of PGD, most, if not all of these factors were seen as necessary but none was seen as sufficient for determining whether a genetic condition was labelled ‘serious’. This, however, is changing as impact on health or severity of symptoms is coming to eclipse the other considerations. This paper investigates how age of onset (primarily in the context of the United Kingdom (UK)) has become considerably less significant as a criterion for determining ethically acceptable applications of PGD. Having moved off the threshold of permitting PGD testing for only fatal (or seriously debilitating), early-onset diseases, I will investigate reasons for why age of onset will not do any work to discriminate between which adult-onset diseases should be considered serious or not. First I will explain the rationale underpinning age of onset as a factor to be weighed in making determinations of seriousness. Next I will challenge the view that later-onset conditions are less serious for being later than earlier-onset conditions. The final section of the paper will discuss some of the broader disability concerns at stake in limiting access to PGD based upon determinations of the ‘seriousness’ of genetic conditions. Instead of advocating a return to limiting PGD to only early-onset conditions, I conclude that the whole enterprise of trying to draw lines of what is to count as a ‘serious’ condition is itself problematic and in certain ways morally misleading. (shrink)

The placenta invades the adjacent uterus and controls the maternal immune system, like a cancer invades surrounding organs and suppresses the local immune response. Intriguingly, placental and cancer cells are globally hypomethylated and share an epigenetic phenomenon that is not well understood – they fail to silence repetitive DNA sequences that are silenced in healthy somatic cells. In the placenta, hypomethylation of retrotransposons has facilitated the evolution of new genes essential for placental function. In cancer, hypomethylation is thought to contribute (...) to activation of oncogenes, genomic instability, and retrotransposon unsilencing; the latter, we postulate, is possibly the most important consequence. Activation of placental retrotransposon-derived genes in cancer underpins our hypothesis that hypomethylation of these genes drives cancer cell invasion. This alludes to an interesting paradox, that while placental retrotransposon-derived genes are essential for promoting early hominid life, the same genes promote disease-susceptibility and death through cancer. Placental and cancer cells fail to silence retrotransposons that are normally silenced in healthy tissues. This has created new genes that are essential for placental function, yet they are also expressed in cancer. We hypothesize that active retrotransposons are a double-edged sword, contributing both adaptive and deleterious functions to biology. (shrink)

DNA copy number variation (CNV) represents a considerable source of human genetic diversity. Recently,1 a global map of copy number variation in the human genome has been drawn up which reveals not only the ubiquity but also the complexity of this type of variation. Thus, two human genomes may differ by more than 20 Mb and it is likely that the full extent of CNV still remains to be discovered. Nearly 3000 genes are associated with CNV. This high degree of (...) variability with regard to gene copy number between two individuals challenges definitions of normality. Many CNVs are located in regions of complex genomic structure and this currently limits the extent to which these variants can be genotyped by using tagging SNPs. However, some CNVs are already amenable to genome‐wide association studies so that their influence on human phenotypic diversity and disease susceptibility may soon be determined. BioEssays 29:311–313, 2007. © 2007 Wiley Periodicals, Inc. (shrink)